Cannabinoid receptor antagonists

- Eli Lilly and Company
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Claims

1. A method of antagonising one or more of the actions of anandamide at cannabinol-1 receptors in a mammal, which comprises administering an effective amount of a compound of formula ##STR9## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

2. A method as claimed in claim 1, in which R.sup.2 is methyl or methoxy and R.sup.3 is methoxy.

3. A method as claimed in claim 2, in which R.sup.1 is methoxy, trifluoromethylsulfonyloxy, hydroxy or cyano.

4. A method as claimed in claim 3, in which R.sup.1 is cyano.

5. A method as claimed in claim 4, in which R.sup.2 is methoxy and R.sup.5 is --O--.

6. A method as claimed in claim 4, in which R.sup.2 is methyl and R.sup.5 is --O--.

7. A method as claimed in claim 4, in which R.sup.2 is methoxy and R.sup.5 is --S--.

8. A method of claim 1 wherein the action involves inhibiting neurotransmission by a cannabinoid receptor in a mammal by administering to said mammal an effective amount of a compound of formula ##STR10## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

9. A method of claim 1 wherein the action involves treating depression in a mammal by administering to said mammal an effective amount of a compound of formula ##STR11## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

10. A method of claim 1 wherein the action involves enhancing memory in a mammal by administering to a mammal an effective amount of a compound of formula ##STR12## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

11. A method of claim 1 wherein the action involves increasing alertness in a mammal by administering to a mammal an effective amount of a compound of formula ##STR13## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

12. A method of claim 1 wherein the action involves increasing sensory perception in a mammal by administering to a mammal an effective amount of a compound of formula ##STR14## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

13. A method of claim 1 wherein the action involves increasing cognitive function in a mammal by administering to a mammal an effective amount of a compound of formula ##STR15## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

14. A method of claim 1 wherein the action involves decreasing hallucinatory dementia in a mammal by administering to a mammal an effective amount of a compound of formula ##STR16## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.

15. A method of claim 1 wherein the action involves treating drug induced schizophrenia, which comprises administering to a mammal an effective amount of a compound of formula ##STR17## in which: R.sup.1 is C.sub.1 -C.sub.4 alkoxy, trifluoromethylsulfonyloxy, hydroxy or cyano;

R.sup.2 and R.sup.3 are each independently C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
R.sup.4 is CO, CHOH or CH.sub.2; and
R.sup.5 is O or S, provided that when R.sup.1 is hydroxy, R.sup.5 is O.
Referenced Cited
U.S. Patent Documents
3331854 July 1967 Huffman et al.
3448190 June 1969 Baron et al.
4133814 January 9, 1979 Jones et al.
4358593 November 9, 1982 Jones et al.
4380635 April 19, 1983 Peters
4418068 November 29, 1983 Jones
5223510 June 29, 1993 Gubin et al.
5308866 May 3, 1994 Lesieur et al.
5521198 May 28, 1996 Zuckerman
5534526 July 9, 1996 Culleran
5552415 September 3, 1996 May
Foreign Patent Documents
WO 95/10513 April 1995 WOX
Other references
Patent History
Patent number: 5747524
Type: Grant
Filed: Sep 30, 1996
Date of Patent: May 5, 1998
Assignee: Eli Lilly and Company (Indianapolis, IN)
Inventors: George J. Cullinan (Trafalgar, IN), Kennan J. Fahey (Indianapolis, IN), Gary A. Koppel (Indianapolis, IN)
Primary Examiner: Deborah Lambkin
Attorneys: Martin A. Hay, David E. Boone
Application Number: 8/724,101
Classifications
Current U.S. Class: Polycyclo Ring System Having The Hetero Ring As One Of The Cyclos (514/443)
International Classification: A61K 3138;